This is an application for a K05 - Senior Scientist Award. The candidate, Dr. Sabita Roy holds a Ph.D. degree from the University of Kansas, Lawrence, and is a Professor in the Basic and translational Division in the Department of Surgery, University of Minnesota. She is currently funded by three independent grants; 1) R01 DA12104: Opioid Abuse, Opportunistic Infection and NeuroAIDS : These studies are designed to investigate if opioid drug abuse and HIV-proteins can either independently or synergistically modulate neuropathogenesis in a S. pneumoniae co-infection model. 2) R01DA031202: Role of microRNAs' in opioid drug abused induced persistent inflammation and HIV Disease Progression. In this project we test the hypothesis that suppression of LPS induced induction of miR-155 and miR-146a, by Morphine and TAT, deregulates the inhibitory feedback loop thus resulting in sustained Toll-Like-Receptor (TLR4) expression and signaling. 3) R01DA022935: Morphine, HIV proteins, wound healing and Infection: The focus of this proposal is to investigate the mechanism by which chronic morphine treatment delays wound healing and if HIV infection further exacerbates the healing process. This K05 award will provide the candidate with release time to expand her research skills and enhance her ability for scientific investigations and mentoring future scientists in drug abuse research. The long-term research goal of the candidate is to explore the molecular and cellular mechanism involved in morphine induced immunosuppression and increased susceptibility to opportunistic infections such as S. pneumonia and HIV/AIDS. The major goal of the current application is to train in HIV/AIDS research as it relates to drug abuse and incorporate this line of research into her ongoing research projects and to introduce state of the art research strategies. To achieve this goal, release time will be utilized for collaborations with HIV/AIDS researchers and researchers with microRNA and TLR expertise. The K05 Award will facilitate this by relieving considerable amount of teaching and administrative duties. This plan has the full support of the Department of Surgery and the University of Minnesota. PUBLIC HEALTH RELEVANCE: The latest statistics on the world epidemic of AIDS & HIV (UNAIDS/WHO, November 2005) report that at least 40 million people are infected with HIV with nearly 6 million cases of AIDS world-wide. There is a strong correlation between chronic drug use and increased susceptibility to HIV infection. Chronic drug users account for approximately a third of all cases of AIDS in the USA and the progression to AIDS dementia is markedly accelerated in opiate drug abusers. This proposal postulates that modulation of microRNAs and Toll like receptors by opioid drug abuse and HIV1-TAT may be a plausible mechanism for the persistent immune activation in these patients. Until now there are no published studies implicating miRs to TLRs' in the dysregulated immune activation observed in HIV infected drug abusing population. These studies will allow for the delineation of the mechanisms and allow for the development of new therapeutic strategies to attenuate immune activation and reverse HIV disease progression both in HIV infected patients and in HIV infected drug abusing population.